Abstract The abuse of substituted cathinones, the main psychoactive components of ?bath salts? and other illicit preparations, has emerged as a persistent public health concern over the past decade. Substituted cathinones, like other phenethylamines including methamphetamine (MA) or (+/-)-3,4-methylenedioxymethamphetamine (MDMA), produce their psychoactive effects through monoaminergic actions resulting from their ability to either block the reuptake or increase the release of neuronal dopamine (DA) and/or serotonin (5-HT). New cathinones are continually being introduced into the underground drug market and differ in one or more structural features, but the balance of neurochemical activity at DA and/or 5-HT transporters is thought to be a key feature that mediates the expression of their MA- or MDMA-like effects (i.e., stimulant or entactogen). However, little is known about how substituted cathinones alter neural activity and whether, like their abuse-related behavioral effects, regional patterns of activation may be related to the balance of their monoaminergic actions. This application, in response to PAR 18-510, is designed to address this issue and proposes cutting-edge, integrated behavioral pharmacology and neuroimaging studies in nonhuman primates to examine the abuse-related behavioral and neural effects of substituted cathinones that vary in selectivity for DA and 5-HT release. First, as drug history is known to play an important role in individual vulnerability to different types of drug abuse and relapse, substituted cathinones will be compared in different groups of both male and female subjects that discriminate or self- administer either MA (DA-selective) or MDMA (5-HT-selective). Next, using well-validated and translationally- relevant animal behavioral models, the subjective, reinforcing, and relapse-inducing (reinstatement) effects of selected cathinones will be compared to those of MA and MDMA. Finally, awake fMRI studies, conducted at ultra-high field strength (9.4T), will be employed in the same subjects to identify key features in the patterns of regional brain activity (neural signature) produced by substituted cathinones that may be related to their MA-like or MDMA-like abuse-related effects. Overall, our planned studies will yield key insights to improve our understanding of the roles of drug history and sex in the abuse-related behavioral effects and neural signatures of different types of synthetic cathinones and, more generally, abused drugs with DA- and/or 5-HT-mediated actions. Such information is essential for accelerating the development of novel treatment strategies for the management of addiction to cathinones and other monoaminergic drugs.